Diagnostic performance of 3.0 Tesla diffusion tensor imaging in the assessment of brain stem glioma grading.

Purpose: This study aimed to investigate the role of 3 Tesla Dif-fusion tensor imaging (DTI) in the assessment of brainstem glioma (BSG) grading. Materials and methods: The study comprised 22 patients, including pathology-proven 6 brainstem low-grade gliomas (BS-LGG) and 16 brainstem high-grade gliomas (BS-HGG). Characteristics including age, gender, fractional anisotropy (FA), mean diffusivity (MD) of the tumor, peritumoral region, and the ratio of tumor FA to parenchymal FA, as well as tumor MD to parenchymal MD (rFA and rMD), were compared using Mann-Whitney U test, Shapiro-Wilk test, and Chi-square test. Receiver operating characteristic (ROC) curve analysis was used in the study to determine cut-off values and diagnostic values for grading brainstem gliomas (BSG) using diffusion tensor imaging (DTI). Results: Our study revealed no significant difference in age and gender between the BS-LGG and BS-HGG groups (p>0.05). Fractional anisotropy (FA) indices on DTI MRI were found to be highly valuable in grading BSG, with an area under the curve (AUC) of 0.958 - 0.979 when using cut-off values of tFA, pFA, rtFA, and rpFA at 0.318, 0.378, 0.424, and 0.517, respectively. Particularly, rtFA demonstrated the hi-ghest diagnostic value with a sensitivity (Se) of 100%, specificity (Sp) of 93.8%, and AUC of 0.079. Conversely, the indices of tumor mean diffusivity (tMD), peritumoral edema region mean diffusivity (pMD), rtMD, and rpMD showed no diagnostic value in grading BSG. Conclusion: The fractional anisotropy (FA) value on DTI between the tumor region and normal brain parenchyma holds significant value in diagnosing brainstem gliomas (BSG) grading, thereby playing a crucial role in treatment planning and predicting outcomes for patients with brainstem gliomas.

Towards Pathogen-Free Coconut Germplasm Exchange.

Coconut (Cocos nucifera L.) is an important palm species that serves as the mainstay of several industries and contributes to the livelihoods of millions of smallholder farmers. International exchange of coconut germplasm has been undertaken for several decades to facilitate the conservation of selected varieties within global genebanks and for the distribution to farmers and scientists. In vitro systems are a convenient and an efficient method for the exchange of coconut germplasm. However, it is possible that these tissue culture systems can transfer lethal pathogens causing a threat to the importing countries. In this review, the following topics are discussed: the major disease-causing agents of concern, the various tissues that could be used for coconut germplasm exchange, and the techniques available for the detection and elimination of disease-causing agents from various transmission systems. Additionally, the lack of clear, science-backed guidelines to facilitate the exchange of in vitro coconut materials is raised, along with recommendations for future studies to ensure the safe movement of coconut germplasm without biosecurity risks.

Activity and function of the endothelial sodium channel is regulated by the effector domain of MARCKS like protein 1 in mouse aortic endothelial cells.

The endothelial sodium channel (EnNaC) plays an important role in regulating vessel stiffness. Here, we investigated the regulation of EnNaC in mouse aortic endothelial cells (mAoEC) by the actin cytoskeleton and lipid raft association protein myristoylated alanine-rich C-kinase substrate like protein 1 (MLP1). We hypothesized that mutation of specific amino acid residues within the effector domain of MLP1 or loss of association between MLP1 and the anionic phospholipid phosphate PIP2 would significantly alter membrane association and EnNaC activity in mAoEC. mAoEC transiently transfected with a mutant MLP1 construct (three serine residues in the effector domain replaced with aspartate residues) showed a significant decrease in EnNaC activity compared to cells transfected with wildtype MLP1. Compared to vehicle treatment, mAoEC treated with the PIP2 synthesis blocker wortmannin showed less colocalization of EnNaC and MLP1. In other experiments, Western blot and densitometric analysis showed a significant decrease in MLP1 and caveloin-1 protein expression in mAoEC treated with wortmannin compared to vehicle. Finally, wortmannin treatment decreased sphingomyelin content and increased membrane fluidity in mAoEC. Taken together, our results suggest constitutive phosphorylation of MLP1 attenuates the function of EnNaC in aortic endothelial cells by a mechanism involving a decrease in association with MLP1 and EnNaC at the membrane, while deletion of PIP2 decreases MARCKS expression and overall membrane fluidity.

Knowledge of Medical Education on Maternal and Child Primary-Care Among Physicians: A Cross-Sectional Study.

Objectives: To assess the pre-training knowledge of Commune Health Stations (CHSs) physicians in Vietnam on pregnancy and child care. Methods: A cross-sectional study was conducted and a pre-training questionnaire was administered with physicians working at CHSs in three mountainous provinces of northern Vietnam. Calculated mean knowledge score and estimated adjusted odds ratios (AOR) to compare the relative odds of occurrence of the outcome "answering more than half of questions correct," given exposure to the physicians' characteristics. Results: A total of 302 CHS physicians participated. The mean number of correct answers across all participants was 5.4 out of 11. Female physicians are 2.20 (95% CI: 1.35-3.59, p = 0.002) times more likely to answer correctly than their male counterparts. Physicians aged 35 years or more were significantly less likely to answer correctly (AOR 0.35, 95% CI: 0.15-0.81, p = 0.014). Conclusion: The study found that participating physicians possessed relatively low knowledge of pregnancy and child care. The study also found significant disparities in this knowledge according to the physicians' characteristics. Thus, it is recommended the requirement for continuing targeted medical education to improve doctors' proficiency in these areas.

Evaluation of screening algorithms to detect rectal colonization with carbapenemase-producing Enterobacterales in a resource-limited setting.

Objectives: To improve and rationalize the detection of carbapenemase-producing Enterobacterales (CPE) in rectal swabs in a high-prevalence and resource-constrained setting, addressing surveillance challenges typically encountered in laboratories with limited resources. Methods: A point prevalence survey (PPS) was conducted on 15 August 2022, in a provincial children's hospital in northern Vietnam. Rectal swab samples of all admitted children were collected and plated on a selective medium for carbapenem-resistant Enterobacterales (CRE). Species identification and antimicrobial susceptibility testing (AST) were performed by MALDI-TOF, and VITEK2 XL and interpreted according to CLSI breakpoints (2022). Carbapenemases were detected by the carbapenem inactivation method (CIM) and quantitative real-time PCR (qRT-PCR). Results: Rectal swab samples were obtained from 376 patients. Of 178 isolates growing on the CRE screening agar, 140 isolates were confirmed as Enterobacterales of which 118 (84.3%) isolates were resistant to meropenem and/or ertapenem. CIM and PCR showed that 90/118 (76.3%) were carbapenemase producers. Overall, 83/367 (22.6%) were colonized by CPE. Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae complex were the most common CPE detected, with NDM as the predominant carbapenemase (78/90; 86.7%). Phenotypic resistance to meropenem was the best predictor of CPE production (sensitivity 85.6%, specificity 100%) compared with ertapenem resistance (95.6% sensitivity, 36% specificity). CIM was 100% concordant with PCR in detecting carbapenemases. Conclusions: These findings underscore the effectiveness of meropenem resistance as a robust indicator of the production of carbapenemases and the reliability of the CIM method to detect such carbapenemases in resource-limited settings where the performance of molecular methods is not possible.

Daily oral administration of probiotics engineered to constantly secrete short-chain fatty acids effectively prevents myocardial injury from subsequent ischemic heart disease.

AIM: Given the extremely limited regeneration potential of the heart, one of the most effective strategies to reduce the prevalence and mortality of coronary artery disease is prevention. Short-chain fatty acids (SCFAs), which are by-products of beneficial probiotics, have been reported to possess cardioprotective effects. Despite their beneficial roles, delivering SCFAs and maintaining their effective concentration in plasma present major challenges. Therefore, in the present study, we aimed to devise a strategy to prevent coronary heart disease effectively by using engineered probiotics to continuously release SCFAs in vivo. METHODS AND RESULTS: We engineered a novel probiotic cocktail, EcN_TL, from the commercially available Escherichia coli Nissle 1917 strain to continuously secrete SCFAs by introducing the propionate and butyrate biosynthetic pathways. Oral administration of EcN_TL enhanced and maintained an effective concentration of SCFAs in the plasma. As a preventative strategy, we observed that daily intake of EcN_TL for 14 days prior to ischemia-reperfusion injury significantly reduced myocardial injury and improved cardiac performance compared to EcN administration. We uncovered that EcN_TL's protective mechanisms included reducing neutrophil infiltration into the infarct site and promoting the polarization of wound-healing macrophages. We further revealed that SCFAs at plasma concentration protected cardiomyocytes from inflammation by suppressing the NF-κB activation pathway. CONCLUSIONS: These data provide strong evidence to support the use of SCFA-secreting probiotics to prevent coronary heart disease. Since SCFAs also play a key role in other metabolic diseases, EcN_TL can potentially be used to treat a variety of other diseases.

Noncanonical microprotein regulation of immunity.

The immune system is highly regulated but, when dysregulated, suboptimal protective or overly robust immune responses can lead to immune-mediated disorders. The genetic and molecular mechanisms of immune regulation are incompletely understood, impeding the development of more precise diagnostics and therapeutics for immune-mediated disorders. Recently, thousands of previously unrecognized noncanonical microprotein genes encoded by small open reading frames have been identified. Many of these microproteins perform critical functions, often in a cell- and context-specific manner. Several microproteins are now known to regulate immunity; however, the vast majority are uncharacterized. Therefore, illuminating what is often referred to as the "dark proteome," may present opportunities to tune immune responses more precisely. Here, we review noncanonical microprotein biology, highlight recently discovered examples regulating immunity, and discuss the potential and challenges of modulating dysregulated immune responses by targeting microproteins.

Serum proteome signatures associated with ileal and colonic ulcers in Crohn's disease.

At a clinical level, ileal and colonic Crohn's disease (CD) are considered as separate entities. These subphenotypes need to be better supported by biological data to develop personalised medicine in CD. To this end, we combined different technologies (proximity extension assay, selected reaction monitoring, and high-sensitivity turbidimetric immunoassay (hsCRP)) to measure 207 immune-related serum proteins in CD patients presenting no endoscopic lesions (endoscopic remission) (n = 23), isolated ileal ulcers (n = 17), or isolated colonic ulcers (n = 16). We showed that isolated ileal ulcers and isolated colonic ulcers were specifically associated with 6 and 18 serum proteins, respectively: (high level: JUN, CNTNAP2; low level: FCRL6, LTA, CLEC4A, NTF4); (high level: hsCRP, IL6, APCS, CFB, MBL2, IL7, IL17A, CCL19, CXCL10, CSF3, IL10, CLEC4G, MMP12, VEGFA; low level: CLEC3B, GSN, TNFSF12, TPSAB1). Isolated ileal ulcers and isolated colonic ulcers were detected by hsCRP with an area under the receiver operating characteristics curve of 0.64 (p-value = 0.07) and 0.77 (p-value = 0.001), respectively. We highlighted distinct serum proteome profiles associated with ileal and colonic ulcers in CD, this finding might support the development of therapeutics and biomarkers tailored to disease location. SIGNIFICANCE: Although ileal and colonic Crohn's disease present important clinical differences (eg, progression, response to treatment and reliability of biomarkers), these two entities are managed with the same therapeutic strategy. The biological specificities of ileal and colonic Crohn's disease need to be better characterised to develop more personalised approaches. The present study used robust technologies (selected reaction monitoring, proximity extension assays and turbidimetric immunoassay) to quantify precisely 207 serum immune-related proteins in three groups of Crohn's disease patients presenting: 1) no endoscopic lesions (endoscopic remission) (n = 23); 2) isolated ileal ulcers (n = 17); 3) isolated colonic ulcers (n = 16). We found distinct serum proteome signatures associated with ileal and colonic ulcers. Our findings could foster the development of biomarkers and treatments tailored to Crohn's disease location.

A SARS-CoV-2 recombinant spike protein vaccine (S-268019-b) for COVID-19 prevention during the Omicron-dominant period: A phase 3, randomised, placebo-controlled clinical trial.

Clinical trials of new vaccines based on existing variants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) are often impacted by the emergence of new virus variants. We evaluated the efficacy, immunogenicity, and safety of S-268019-b, a recombinant spike protein subunit vaccine based on the ancestral strain, for preventing symptomatic coronavirus disease 2019 (COVID-19) during the Omicron (BA.2)-dominant period in Vietnam. In this multicentre, phase 3, randomised (2:1), observer-blind, placebo-controlled crossover study, participants received 2 intramuscular doses (28 days apart) of either 10 µg of S-268019-b (Recombinant S-protein vaccine) or placebo. The primary endpoint was incidence of laboratory-confirmed symptomatic COVID-19 before crossover, with onset within 14 days following the second dose, in participants who were seronegative and reverse transcription polymerase chain reaction (RT-PCR)-negative at baseline. The secondary endpoints included immunogenicity and safety. In total, 8,594 participants were randomised (S-268019-b [n = 5,727]; placebo [n = 2,867]). Vaccine efficacy versus placebo was 39·1 % (95 % confidence interval [CI]:26·6-49·5; one-sided P = 0·0723). The incidence rate (95 % CI) of symptomatic COVID-19 was 776·41/1,000 person-years (682·04-880·19) in the S-268019-b group and 1272·87/1,000 person-years (1101·32-1463·57) in the placebo group. The geometric mean titres (95 % CI) of the SARS-CoV-2 neutralising antibody increased on Day 57 versus baseline with S-268019-b (34·66 [27·04-44·41] versus 2·50 (non-estimable) but not with placebo. There were no safety concerns regarding S-268019-b. S-268019-b did not demonstrate the targeted efficacy threshold against symptomatic COVID-19; however, findings were comparable with other prophylactic vaccines based on ancestor strain during the Omicron-dominant period. S-268019-b demonstrated immunogenicity and was well-tolerated. ClinicalTrials.gov identifier: NCT05212948.

Partial Fourier in the presence of respiratory motion in prostate diffusion-weighted echo planar imaging.

PURPOSE: To investigate the effect of respiratory motion in terms of signal loss in prostate diffusion-weighted imaging (DWI), and to evaluate the usage of partial Fourier in a free-breathing protocol in a clinically relevant b-value range using both single-shot and multi-shot acquisitions. METHODS: A controlled breathing DWI acquisition was first employed at 3 T to measure signal loss from deep breathing patterns. Single-shot and multi-shot (2-shot) acquisitions without partial Fourier (no pF) and with partial Fourier (pF) factors of 0.75 and 0.65 were employed in a free-breathing protocol. The apparent SNR and ADC values were evaluated in 10 healthy subjects to measure if low pF factors caused low apparent SNR or overestimated ADC. RESULTS: Controlled breathing experiments showed a difference in signal coefficient of variation between shallow and deep breathing. In free-breathing single-shot acquisitions, the pF 0.65 scan showed a significantly (p < 0.05) higher apparent SNR than pF 0.75 and no pF in the peripheral zone (PZ) of the prostate. In the multi-shot acquisitions in the PZ, pF 0.75 had a significantly higher apparent SNR than 0.65 pF and no pF. The single-shot pF 0.65 scan had a significantly lower ADC than single-shot no pF. CONCLUSION: Deep breathing patterns can cause intravoxel dephasing in prostate DWI. For single-shot acquisitions at a b-value of 800 s/mm2, any potential risks of motion-related artefacts at low pF factors (pF 0.65) were outweighed by the increase in signal from a lower TE, as shown by the increase in apparent SNR. In multi-shot acquisitions however, the minimum pF factor should be larger, as shown by the lower apparent SNR at low pF factors.

Motion-induced phase-corrected homodyne reconstruction for partial Fourier single-shot diffusion-weighted echo planar imaging of the liver.

Partial Fourier encoding is popular in single-shot (ss) diffusion-weighted (DW) echo planar imaging (EPI) because it enables a shorter echo time (TE) and, hence, improves the signal-to-noise-ratio. Motion during diffusion encoding causes k-space shifting and dispersion, which compromises the quality of the homodyne reconstruction. This work provides a comprehensive understanding of the artifacts in homodyne reconstruction of partial Fourier ss-DW-EPI data in the presence of motion-induced phase and proposes the motion-induced phase-corrected homodyne (mpc-hdyne) reconstruction method to ameliorate these artifacts. Simulations with different types of motion-induced phase were performed to provide an understanding of the potential artifacts that occur in the homodyne reconstruction of partial Fourier ss-DW-EPI data. To correct for the artifacts, the mpc-hdyne reconstruction is proposed. The algorithm recenters k-space, updates the partial Fourier factor according to detected global k-space shifts, and removes low-resolution nonlinear phase before the conventional homodyne reconstruction. The mpc-hdyne reconstruction is tested on both simulation and in vivo data. Motion-induced phase can cause signal overestimation, worm artifacts, and signal loss in partial Fourier ss-DW-EPI data with the conventional homodyne reconstruction. Simulation and in vivo data showed that the proposed mpc-hdyne reconstruction ameliorated artifacts, yielding higher quality DW images compared with conventional homodyne reconstruction. Based on the understanding of the artifacts in homodyne reconstruction of partial Fourier ss-DW-EPI data, the mpc-hdyne reconstruction was proposed and showed superior performance compared with the conventional homodyne reconstruction on both simulation and in vivo data.

Identification of potential FAK inhibitors using mol2vec molecular descriptor-based QSAR, molecular docking, ADMET study, and molecular dynamics simulation.

This study aims to identify potential focal adhesion kinase (FAK) inhibitors through an integrated computational approach, combining mol2vec descriptor-based QSAR, molecular docking, ADMET study, and molecular dynamics simulation. A dataset of 437 compounds with known FAK inhibitory activities was used to develop QSAR models using machine learning algorithms combined with mol2vec descriptors. Subsequently, the most promising compounds were subjected to molecular docking against FAK to evaluate their binding affinities and key interactions. ADMET study and molecular dynamics simulation were also employed to investigate the pharmacokinetic, drug-like properties, and the stability of the protein-ligand complexes. The results showed that the mol2vec descriptor-based QSAR model established by support vector regression demonstrated good predictive performance (R2 = 0.813, RMSE = 0.453, MAE = 0.263 in case of training set, and R2 = 0.729, RMSE = 0.635, MAE = 0.477 in case of test set), indicating their reliability in identifying potent FAK inhibitors. Using this QSAR model and molecular docking, compound 21 (ZINC000004523722) was identified as the most potential compound, with predicted logIC50 value and binding energy of 2.59 and - 9.3 kcal/mol, respectively. The results of molecular dynamics simulation and ADMET study also further suggested its potential as a promising drug candidate. However, because our research was merely theoretical, additional in vitro and in vivo studies are required for the verification of these results.

Antiplatelet and Anticoagulant Effects of Two New Phenylpropanoid Sucrose Esters and Other Secondary Metabolites from the Aerial Part of Canna edulis.

This study isolated pure compounds from Canna edulis aerial parts and assessed their antiplatelet and anticoagulant potential. Structural elucidation resulted in the identification of two new compounds: caneduloside A (1) and caneduloside B (2), and eleven known compounds: 6'-acetyl-3,6,2'-tri-p-coumaroyl sucrose (3), 6'-acetyl-3,6,2'-triferuloyl sucrose (4), tiliroside (5), afzelin (6), quercitrin (7), 2-hydroxycinnamaldehyde (8), cinnamic acid (9), 3,4-dimethoxycinnamic acid (10), dehydrovomifoliol (11), 4-hydroxy-3,5-dimethoxybenzaldehyde (12), and (S)-(-)-rosmarinic acid (13). Compounds 3, 4, 6-9, 13 were previously reported for antithrombotic properties. Hence, antithrombotic tests were conducted for 1, 2, 5, 10-12. All tested compounds demonstrated a dose-dependent antiaggregatory effect, and 10 and 12 were the most potent for both ADP and collagen activators. Additionally, 10 and 12 showed anticoagulant effects, with prolonged prothrombin time and activated partial thromboplastin time. The new compound 1 displayed antiplatelet and anticoagulant activity, while 2 mildly inhibited platelet aggregation. C. edulis is a potential source for developing antithrombotic agents.

Evaluation of Factors Influenced on the Effectiveness of Percutaneous Nephrolithotomy.

Background: Generally, there are many methods for the treatment of urinary stones, of which percutaneous nephrolithotomy (PCNL) is a minimally invasive and highly effective method, and now become the first-line management for urinary stones, especially in the cases of complex stones and staghorne calculi. Accurate assessment of stone location, stone morphology, degree of hydronephrosis as well as urinary system abnormalities is extremely important in the percutaneous nephrolithotomy strategy. Objective: The aim of this study was to evaluate the S.T.O.N.E score as well as other factors that influenced the effectiveness of PCNL. Methods: Descriptive study on 71 patients with kidney stones, who underwent multi-slice CT scan of the urinary system before PCNL and then PCNL at Hanoi Medical University Hospital from July 2022 to July 2023. All patients received the informed consent and agreed to participate in the study. The factors included the stone area, the track length (from the skin surface to the stone central), the degree of urinary tract dilatation, the number of involved calyces, the density of stone, the renal parenchyma thickness, the ureteral wall thickness and fat infiltration measured on MSCT non-contrast phase. These factors were used to predict the effectiveness of PCNL including the stone clearance rate (SCR) and the operation time. Results: The mean age of the patient group was 53.8±12.3. The male/female ratio was 1.54. There was a significant difference (p<0.05) between the following factors and the operation time: the stone area (<400, 400-799, 800-1599 and >1600 mm2), the degree of urinary tract dilatation (no or might and moderate or severe dilatation), the number of involved calyces (≤ 2, 3 and staghorne calculi), the renal parenchyma thickness (<18 mm and ≥18mm). In contrast, there were no significant differences between the following factors and the surgery time (p>0.05): the track length (<100 and ≥100 mm), and the stone density (<950 and ≥950 HU). Regarding the S.T.O.N.E score (included five factors: Size, Track length, Obstruction, Number of involved calyces, and Evaluation of stone density), there was a strong correlation between S.T.O.N.E score and the surgery time (p<0.001, r=0.94), and the SCR (p=0.001, r=-0.97). Conclusion: The evaluation of these factors played an important role in the prediction of the effectiveness of PCNL.

Robust-optimal control of rotary inverted pendulum control through fuzzy descriptor-based techniques.

Expanding upon the well-established Takagi-Sugeno (T-S) fuzzy model, the T-S fuzzy descriptor model emerges as a robust and flexible framework. This article introduces the development of optimal and robust-optimal controllers grounded in the principles of stability control and fuzzy descriptor systems. By transforming complicated inequalities into linear matrix inequalities (LMI), we establish the essential conditions for controller construction, as delineated in theorems. To substantiate the utility of these controllers, we employ the rotary inverted pendulum as a testbed. Through diverse simulation scenarios, these controllers, rooted in fuzzy descriptor systems, demonstrate their practicality and effectiveness in ensuring the stable control of inverted pendulum systems, even in the presence of uncertainties within the model. This study highlights the adaptability and robustness of fuzzy descriptor-based controllers, paving the way for advanced control strategies in complex and uncertain environments.

Impact of Cumulative 6†mg/kg Antithymocyte Globulin on Early Posttransplant Outcomes in Kidney Transplant Recipients with Delayed Graft Function.

Introduction: Delayed graft function in kidney transplant is associated with an increased risk of rejection and graft loss. Use of rabbit antithymocyte globulin induction in delayed graft function has been correlated with less rejection compared to basiliximab, but optimal dosing remains unknown. Program Evaluation Aims: The purpose of this evaluation was to retrospectively assess the short-term effectiveness and tolerability of a clinical protocol that increased the net state of immunosuppression in delayed graft function kidney transplant recipients using cumulative 6 mg/kg rabbit antithymocyte globulin induction. Design: This retrospective cohort included 88 kidney transplant recipients with delayed graft function, transplanted between January 2017 and March 2021, who either received cumulative 4.5 mg/kg pre-protocol or 6 mg/kg post-protocol rabbit antithymocyte globulin. Outcomes evaluated were biopsy-proven acute rejection and incidence of graft loss, infection, and cytopenia at 6 months. Results: A significant reduction of biopsy-proven acute rejection incidence occurred post-protocol implementation (10/33, 30.3% vs 6/55, 10.9%; P = .04). Of those with rejection, significantly less post-protocol patients were classified as acute cellular rejection (9/10, 90.0% vs 2/6, 33.3%; P = .04). No death-censored graft loss was observed in either group. Rates of cytopenia and infection were similar pre- versus post-protocol implementation. Conclusion: Increasing the exposure to rabbit antithymocyte globulin and maintenance immunosuppression in delayed graft function kidney transplant recipients was tolerable and significantly reduced rejection occurrence at 6 months.

Mezagitamab in systemic lupus erythematosus: clinical and mechanistic findings of CD38 inhibition in an autoimmune disease.

OBJECTIVE: To evaluate safety and mechanism of action of mezagitamab (TAK-079), an anti-CD38 monoclonal antibody, in patients with moderate to severe systemic lupus erythematosus (SLE). METHODS: A phase 1b double-blind, placebo-controlled, multicentre study was conducted in patients with SLE receiving standard background therapy. Eligible patients were adults who met the 2012 SLICC or ACR criteria for diagnosis, had a baseline SLE Disease Activity Index 2000 (SLEDAI-2K) score of ≥6 and were positive for anti-double-stranded DNA antibodies and/or anti-extractable nuclear antigens antibodies. Patients received 45 mg, 90 mg or 135 mg of mezagitamab or placebo every 3 weeks over 12 weeks. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and pharmacodynamics. Exploratory assessments included disease activity scales, deep immune profiling and interferon pathway analysis. RESULTS: 22 patients received at least one dose of either mezagitamab or placebo. In patients exposed to mezagitamab (n=17), drug was well tolerated. Adverse event (AEs) were balanced across treatment groups, with no treatment emergent AEs exceeding grade 2. Responder analyses for Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and SLEDAI-2K did not reveal any observable differences across treatment groups. However, there was a trend for more profound skin responses among patients with higher CLASI scores (>10) at baseline. Pharmacodynamic analysis showed median CD38 receptor occupancy up to 88.4% on CD38+ natural killer cells with concurrent depletion of these cells up to 90% in the 135 mg group. Mean reductions in IgG and autoantibodies were less than 20% in all dose groups. Cytometry by time of flight and type 1 interferon gene analysis revealed unique fingerprints that are indicative of a broad immune landscape shift following CD38 targeting. CONCLUSIONS: Mezagitamab had a favourable safety profile in patients with moderate to severe SLE and elicited a pharmacodynamic effect consistent with CD38+ cell depletion. These findings reveal novel insights into the drug's mechanism of action and support the continued investigation of mezagitamab in autoimmune diseases.